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The mechanisms and brain circuitry that render genetically epilepsy-prone rats (GEPRs) susceptible to acoustically induced seizures are not completely known. The present study explores the neuroanatomy of acoustically induced seizures by immunohistochemical analysis of the proto-oncoprotein fos after intense acoustic stimulation (AS) with and without seizures. Acoustic stimulation induced tonic convulsions in GEPR-9s, but not in control rats. Locations of brain nuclei showing fos-like immunoreactive (FLI) neurons following AS with and without seizures were mapped. Semiquantitative methods were used to compare FLI neuron numerical densities in AS control rats and GEPRs. Many brain areas exhibited profound FLI in AS control rats and GEPRs. Unexpectedly, the cochlear nuclei and the central nucleus of the inferior colliculi (ICc), both of which are requisite for AGS initiation, exhibited a diminished fos expression in animals having seizures compared to AS controls. In contrast, GEPRs displayed a significant increase in FLI neurons within the dorsal cortex of the IC (ICd) compared to AS controls. This finding may suggest a seizure-related amplification of the auditory signal between the ICc and the ICd. Other nuclei, known to be involved in auditory transmission (i.e., superior olivary complex; trapezoid nucleus; dorsal nucleus of the lateral lemniscus, DNLL), did not show differential FLI densities between seizure and AS control animals. In contrast, seizure-induced FLI was observed in many nonauditory brain nuclei. Of particular interest was the identification of an intensely labeled nucleus in the GEPR. This nucleus resides in the most posterior and dorsal-lateral part of the pedunculopontine tegmental nucleus-pars compacta (PPTn-pc) immediately adjacent to the DNLL and extends posteriorly into the superior lateral subnucleus of the lateral parabrachial area (SLPBn). Therefore, we have tentatively termed this nucleus the PPSLPBn. The PPSLPBn lies in a region previously described as a mesencephalic locomotor region and a suspected functional involvement of this nucleus in display of seizure activity is under investigation. Other brain stem nuclei showing differential fos expression between GEPRs and AS control rats are also described.

Formic acid is the toxic metabolite in methanol poisoning. Permanent visual damage in methanol-intoxicated humans and non-human primates has been associated with prolonged exposures (> 24 hr) to blood formate concentrations in excess of 7 mM; however, little information is available on the toxicity associated with chronic low-level or repeated exposure to methanol. The present studies compared the effects on retinal function and structure of rapidly increasing formate concentrations typical of acute methanol intoxication with low-level plateau formate concentrations more likely to be generated by subacute or chronic methanol exposure. Rats that accumulated formate concentrations of 8-15 mM developed metabolic acidosis, retinal dysfunction, and retinal histopathologic changes. Retinal dysfunction was measured as reductions in the a- and b-waves of the electroretinogram that occurred coincident with blood formate accumulation. Histopathologic studies revealed vacuolation in the retinal pigment epithelium and photoreceptor inner segments. Rats exposed to formate concentrations ranging from 4 to 6 mM for 48 hr showed evidence of retinal dysfunction in the absence of metabolic acidosis and retinal histopathology. These data indicate that formic acid generated from methanol oxidation acts as a direct retinal toxin. Formate-induced retinal dysfunction in methanol-intoxicated rats can be produced by steadily increasing concentrations of formate and importantly can also be produced by prolonged exposure to lower concentrations of formate. Our findings substantiate evidence based on clinical case reports and a small number of epidemiological studies and support the hypothesis that the visual system toxicity produced by acute, subacute, or chronic methanol poisoning share a common mechanism.

The effects of pyrethroid insecticides and other sodium channel-specific neurotoxins on synaptosomal membrane potential were investigated in rat and trout brain synaptosomes using the membrane-permeant lipophilic cation [3H]tetraphenylphosphonium (TPP+). Concentration-dependent and tetrodotoxin-sensitive decreases in TPP+ accumulation, indicative of membrane depolarization, were produced by veratridine, aconitine, scorpion (Leiurus quinquestriatus) venom, and type I and type II pyrethroids, in both species. Veratridine, aconitine, and Leiurus venom were more potent and efficacious membrane-depolarizing agents in rat synaptosomes than in trout synaptosomes. Type II (deltamethrin, cypermethrin) pyrethroids produced similar depolarizing responses in rat and trout synaptosomes; however, the 1R-cis-alpha R isomer of deltamethrin, which had no effect on membrane potential in rat synaptosomes, depolarized trout synaptosomes. This isomer of deltamethrin was also shown to produce toxicity in trout, but not in rats. The type I pyrethroids, permethrin and NRDC 157, exhibited significantly greater intrinsic activity in trout brain synaptosomes, producing maximal membrane depolarizations that were three times greater than those observed in rat brain synaptosomes. These results provide evidence of species-specific differences in the membrane-depolarizing properties of pyrethroid insecticides and sodium channel-specific neurotoxins. They also suggest that some of the neurotoxin binding domains of the voltage-sensitive sodium channel in trout brain differ from those in mammalian brain. The hypersensitivity of fish to the neurotoxic actions of pyrethroid insecticides may be related to these differences.